clozapine and nemonapride

Abnormalities in glutamatergic signalling are proposed in schizophrenia in light of the schizophreniform psychosis elicited by NMDA antagonists. The metabotropic glutamate receptor 5 (mGluR5) interacts closely with the NMDA receptor and is implicated in several behavioural endophenotypes of schizophrenia. We have demonstrated that mice lacking mGluR5 have increased sensitivity to the hyperlocomotive effects of the NMDA antagonist MK-801. Mice lacking mGluR5 also show abnormal locomotor patterns, reduced prepulse inhibition (PPI), and deficits on performance of a short-term spatial memory task on the Y-maze. Chronic administration of the antipsychotic drug clozapine ameliorated the locomotor disruption and reversed the PPI deficit, but did not improve Y-maze performance. Chronic clozapine increased NMDA receptor binding ([3H]MK-801) but did not alter dopamine D2 ([3H]YM-09151), 5-HT2A ([3H]ketanserin), or muscarinic M1/M4 receptor ([3H]pirenzepine), binding in these mice. These results demonstrate behavioural abnormalities that are relevant to schizophrenia in the mGluR5 knockout mouse and a reversal of behaviours with clozapine treatment. These results highlight both the interactions between mGluR5 and NMDA receptors in the determination of schizophreniform behaviours and the potential for the effects of clozapine to be mediated by NMDA receptor regulation.

Topics: Animals; Antipsychotic Agents; Autoradiography; Behavior, Animal; Benzamides; Clozapine; Excitatory Amino Acid Antagonists; Exploratory Behavior; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Muscarinic Antagonists; Radioligand Assay; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists; Up-Regulation

Typical antipsychotics such as haloperidol exert their therapeutic effects via blockade of dopamine (DA) D(2) receptors, leading to extrapyramidal symptoms (EPS) in humans and catalepsy in rodents. In contrast, atypical antipsychotics and new generation D(2)/5-HT(1A) antipsychotics have low cataleptogenic potential. However, there has been no systematic comparative study on the effects of these different classes of antipsychotics in non-human primates, a species displaying a more sophisticated repertoire of behavioural/motor activity than rats. Once weekly, six young adult female non-haloperidol-sensitised cynomolgus monkeys were treated i.m. with a test compound and videotaped to score catalepsy-associated behaviour (CAB: static postures, unusual positions and crouching). Haloperidol, risperidone, olanzapine, nemonapride and remoxipride induced, to different extents, an increase in unusual positions (a response akin to dystonia), some crouching and static postures. In contrast, clozapine, quetiapine, ziprasidone and aripiprazole produced much lower or no unusual positions; clozapine also produced marked increases in static postures and crouching. Among novel D(2)/5-HT(1A) antipsychotics, SLV313 and F15063 augmented the number of unusual positions, albeit at doses 16-63 times higher than those of haloperidol for approximately the same score. SSR181507 and bifeprunox produced moderate static postures, little crouching and negligible unusual positions. These data provide the first comparative analysis in cynomolgus monkeys of EPS liability of conventional, atypical and novel D(2)/5-HT(1A) antipsychotics. They indicate that the latter are less prone than haloperidol to produce CAB, and provide a basis for comparison with rodent catalepsy studies.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antipsychotic Agents; Aripiprazole; Benzamides; Benzodiazepines; Benzoxazoles; Catalepsy; Clozapine; Dibenzothiazepines; Dioxanes; Dopamine Antagonists; Female; Haloperidol; Macaca fascicularis; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Remoxipride; Risperidone; Serotonin Receptor Agonists; Thiazoles; Tropanes; Video Recording

Aripiprazole and the candidate antipsychotics, S33592, bifeprunox, N-desmethylclozapine (NDMC) and preclamol, are partial agonists at D(2) receptors. Herein, we examined their actions at D(2L) and D(3) receptors expressed separately or together in COS-7 cells. In D(2L) receptor-expressing cells co-transfected with (D(3) receptor-insensitive) chimeric adenylate cyclase-V/VI, drugs reduced forskolin-stimulated cAMP production by approximately 20% versus quinpirole (48%). Further, quinpirole-induced inhibition was blunted by aripiprazole and S33592, confirming partial agonist properties. In cells co-transfected with equal amounts of D(2L)and D(3) receptors (1 : 1), efficacies of aripiprazole and S33592 were attenuated. Further, in cells co-transfected with D(2L) and an excess of D(3) receptors (1 : 3), aripiprazole and S33592 were completely inactive, and they abolished the actions of quinpirole. Likewise, bifeprunox, NDMC and preclamol lost agonist properties in cells co-transfected with D(2L)and D(3) receptors. Accordingly, at split D(2trunk)/D(3tail) and D(3trunk)/D(2tail) chimeras, agonist actions of quinpirole were blocked by aripiprazole and S33592 that, like bifeprunox, NDMC and preclamol, were inactive alone. Conversely, when a 12 amino acid sequence in the third intracellular loop of D(3) receptors was replaced by the homologous sequence of D(2L) receptors, aripiprazole, S33592, bifeprunox, NDMC and preclamol inhibited cAMP formation by approximately 20% versus quinpirole (42%). Moreover, at D(2L) receptor-expressing cells co-transfected with modified D(3i3(D2)) receptors, drugs behaved as partial agonists. To summarize, low efficacy agonist actions of aripiprazole, S33592, bifeprunox, NDMC and preclamol at D(2L) receptors are abrogated upon co-expression of D(3) receptors, probably due to physical association and weakened coupling efficacy. These findings have implications for the functional profiles of antipsychotics.

Topics: Adenylyl Cyclases; Animals; Antipsychotic Agents; Aripiprazole; Benzamides; Benzoxazoles; Carrier Proteins; Chlorocebus aethiops; Clozapine; COS Cells; Cricetinae; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Piperazines; Piperidines; Quinolones; Receptors, Dopamine D2; Receptors, Dopamine D3; Transfection

1-(2-ethoxy-phenyl)-4-[3-(3-thiophen-2-yl-isoxazolin-5-yl)-propyl]-piperazine (KCH-1110), has a high affinity for human dopamine D3 (hD3) receptor (Ki=1.28 nM) with about 90-fold selectivity over the human dopamine D2L (hD2L) receptor. Antipsychotic or antidopaminergic activity of KCH-1110 was investigated in the models for the positive symptoms of schizophrenia, apomorphine-induced climbing and cocaine-induced hyperlocomotion, in mice. Intraperitoneal (i.p.) or oral (p.o.) administration of KCH-1110 potently inhibited the apomorphine-induced cage climbing without any rotarod ataxia in mice. Cocaine-induced hyperactivity was also antagonised by KCH-1110. In addition, KCH-1110 attenuated the hypothermia induced by a selective dopamine D3 agonist, 7-OH-DPAT in mice. KCH-1110 did not induce catalepsy in mice, but at much higher doses only a slight catalepsy response was shown. Although high doses of KCH-1110 significantly enhanced serum prolactin secretion in rats, low dose of KCH-1110 did not increase prolactin levels in rats. The present studies, therefore, suggest that KCH-1110 is a potent and relatively selective dopamine D3 receptor antagonist with antipsychotic actions.

Topics: Animals; Antipsychotic Agents; Benzamides; Binding, Competitive; Body Temperature; Catalepsy; Cell Line; Clozapine; Cocaine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Haloperidol; Humans; Hypothermia; Isoxazoles; Male; Mice; Motor Activity; Prolactin; Psychomotor Performance; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Tetrahydronaphthalenes; Thiophenes; Tritium

In situ radioligand binding and quantitative autoradiography have been used to measure the density of striatal D1-like, D2-like, and GABAA receptors in rats treated with haloperidol at 0.01 or 0.1 mg/kg/ day or chlorpromazine, olanzapine or clozapine at 0.1 or 1.0 mg/kg/day for 1, 3 or 7 months. [3H]SCH23390 binding to D1-like receptors was not changed by any drug treatments. There were significant increases in [3H]nemonapride binding to D2-like receptors at different time points due to treatment with haloperidol, chlorpromazine and olanzapine. By contrast, treatment with clozapine and olanzapine caused a time-dependent decrease in [3H]muscimol binding to the GABAA receptor. These data suggest that treatment with atypical antipsychotic drugs, but not typical antipsychotic drugs, affect striatal GABAergic neurons. In addition, it would appear that clozapine might be unique in that it does not increase dopamine-D2 like receptor density at doses which would be predicted to have antipsychotic effects in humans. The extent to which such changes are involved in the therapeutic effects of drugs such as olanzapine and clozapine remains to be determined.

Topics: Animals; Antipsychotic Agents; Benzamides; Benzazepines; Benzodiazepines; Chlorpromazine; Clozapine; Corpus Striatum; Dose-Response Relationship, Drug; Haloperidol; Male; Muscimol; Olanzapine; Pirenzepine; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, GABA-A

Regulation of dopamine receptor subtypes was determined after long-term (8 mo) administration of typical and atypical antipsychotic drugs using 3H-nemonapride, 3H-raclopride, 3H-spiperone, 3H-7-hydroxy-N,N-di-n-propyl-2-aminotetralin, 3H-SCH23390 and 125I-sulpiride in vitro receptor autoradiography. Drug-induced receptor upregulation was remarkably different across the various D2-like receptor radioligands. Chronic haloperidol treatment resulted in a strong increase in 3H-nemonapride, 3H-spiperone and 125I-sulpiride binding to striatal areas, whereas 3H-raclopride binding was marginally affected. Raclopride treatment elevated striatal binding of 3H-nemonapride and 3H-spiperone to a lesser extent, and did not alter 3H-raclopride binding. Clozapine treatment did not affect the binding of the tritiated radioligands. These differences suggest that 3H-nemonapride and 3H-spiperone are binding to an additional subset of D2-like receptors, not recognized by 3H-raclopride. 3H-Nemonapride binding in the presence of 300 nM raclopride uncovered a striatal binding site (designated as D4-like receptor), that was up-regulated after chronic haloperidol, raclopride and clozapine treatment. The 125I-sulpiride binding sites in the prefrontal cortex were also up-regulated by the three antipsychotics. In contrast, 3H-spiperone binding sites were down-regulated in the prefrontal and dorsolateral cortical area. Chronic antipsychotic treatment did not affect Dl-like or D3 dopamine receptor subtype binding.

Topics: Animals; Antipsychotic Agents; Benzamides; Benzazepines; Brain; Clozapine; Corpus Striatum; Haloperidol; Iodine Radioisotopes; Male; Organ Specificity; Raclopride; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Serotonin; Salicylamides; Spiperone; Tetrahydronaphthalenes; Time Factors; Tritium; Up-Regulation

The pharmacological characteristics of two benzamides, YM-43611, a potent and selective dopamine D3 and D4 antagonist, and YM-09151-2 (nemonapride), were compared with two reference antipsychotic agents, haloperidol and clozapine, in terms of modification of c-fos and related gene expression in the rat forebrain. After subcutaneous injection of YM-43611 (1 or 5 mg/kg), nemonapride (4 mg/kg), haloperidol (1 mg/kg), or clozapine (25 mg/kg), Fos immunocytochemistry was employed, and the distributions of Fos-like immunoreactive neurons were compared. As was the case for the two reference antipsychotics, the two benzamides enhanced c-Fos immunoreactivity in a number of forebrain regions. Specifically, like clozapine and nemonapride, YM-43611 significantly increased the number of immunoreactive cells in the nucleus accumbens shell and islands of Calleja. In contrast to clozapine and nemonapride, YM-43611 did not increase c-fos expression in the medial prefrontal cortex. Haloperidol and nemonapride elevated the number of positive cells in the striatum and nucleus accumbens core, whereas clozapine and YM-43611 did not. Clozapine increased the number of Fos-like immunoreactive cells in the lateral septal nucleus and the diagonal band nucleus, but YM-43611, nemonapride, and haloperidol did not. The present findings demonstrate that in comparison with three other drugs, YM-43611 has restricted effects on c-fos expression in the rat forebrain and is active primarily in the shell region of the nucleus accumbens and the islands of Calleja. The ability of YM-43611 to block D3 and D4 receptors may contribute to its unique actions on Fos induction.

Topics: Animals; Benzamides; Clozapine; Dopamine Antagonists; Haloperidol; Immunohistochemistry; Male; Prosencephalon; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, Dopamine D2

5-HT1A receptor agonists are thought to enhance the antipsychotic-like effects of dopamine D2 receptor antagonists while reducing their potential to produce extrapyramidal side effects. Thus, 5-HT1A receptor agonist properties of mixed 5-HT1A receptor agonists/D2 receptor antagonists might be of clinical importance. The antipsychotics, clozapine and nemonapride, and the putative antipsychotic, bromerguride, have intermediate to high affinity for 5-HT1A receptors. The present study examined the 5-HT1A receptor agonist activity of nemonapride and bromerguride, in comparison with clozapine, which has partial 5-HT1A receptor agonist properties in vitro. Here, 5-HT1A receptor activation was examined in vitro, by measuring forskolin-stimulated cAMP accumulation in HeLa cells expressing human 5-HT1A receptors, and in vivo, by using microdialysis to measure the extracellular concentration of hippocampal 5-hydroxytryptamine (5-HT) in rats. Nemonapride markedly decreased both forskolin-stimulated cAMP accumulation and the extracellular concentration of 5-HT; both effects were antagonized by the 5-HT1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY100635). In contrast, clozapine only partially decreased forskolin-stimulated cAMP accumulation and extracellular 5-HT, and only its effects on cAMP accumulation were attenuated by WAY100635. Bromerguride decreased neither forskolin-stimulated cAMP accumulation nor extracellular 5-HT; instead, it antagonized the decrease of cAMP accumulation produced by 5-HT and the decrease of extracellular 5-HT produced by the 5-HT1A agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The selective D2 receptor antagonist, raclopride, affected neither forskolin-stimulated cAMP in vitro nor extracellular 5-HT in vivo. Thus, in contrast with clozapine and bromerguride, only the novel antipsychotic, nemonapride, exhibited marked 5-HT1A receptor agonist properties both in vitro and in vivo; conceivably, these properties may play a role in its preclinical and clinical effects.

Topics: Animals; Antipsychotic Agents; Benzamides; Clozapine; Cyclic AMP; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; HeLa Cells; Hippocampus; Humans; Lisuride; Male; Microdialysis; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin Receptor Agonists

To investigate whether polymorphic forms of the human dopamine D4 receptor have different functional characteristics, we have stably expressed cDNAs of the D4.2, D4.4, and D4.7 isoforms in several cell lines. Chinese hamster ovary CHO-K1 cell lines expressing D4 receptor variants displayed pharmacological profiles that were in close agreement with previous data from transiently expressed D4 receptors in COS-7 cells. Dopamine stimulation of the D4 receptors resulted in a concentration-dependent inhibition of the forskolin-stimulated cyclic AMP (cAMP) levels. The potency of dopamine to inhibit cAMP formation was about twofold reduced for D4.7 (EC50 of approximately 37 nM) compared with the D4.2 and D4.4 variants (EC50 of approximately 16 nM). Antagonists block the dopamine-mediated inhibition of cAMP formation with a rank order of potency of emonapride > haloperidol = clozapine >> raclopride. There was no obvious correlation between the efficacy of inhibition of forskolin-stimulated cAMP levels and the D4 subtypes. Dopamine could completely reverse prostaglandin E2-stimulated cAMP levels for all three D4 receptor variants. Deletion of the repeat sequence does not affect functional activity of the receptor. The data presented indicate that the polymorphic repeat sequence causes only small changes in the ability of the D4 receptor to block cAMP production in CHO cells.

Topics: Animals; Benzamides; Cell Line; CHO Cells; Clozapine; Colforsin; Cricetinae; Cyclic AMP; Dinoprostone; Dopamine; Haloperidol; HeLa Cells; Humans; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D4; Recombinant Proteins; Salicylamides; Spiperone; Transfection

The powerful psychostimulant and positive reinforcing effects of nicotine have been speculated to be mediated by the dopaminergic neurons of the ventral tegemental area (VTA) and their terminals in the nucleus accumbens. To extend our understanding of nicotine and dopamine interactions, we mapped the pattern of c-fos expression in the striatum as an important marker of some of the earliest changes that occur at gene transcription level. Acute nicotine injections in rats led to Fos expression more prominently in the caudatoputamen than in the nucleus accumbens in a dose-dependent fashion. Fos-reactive cells were more prominent in the central and dorsomedial limbic caudatoputamen than in the dorsolateral sensory-motor striatum. Injections of mecamylamine completely blocked nicotine-induced Fos expression. Injections of the selective dopamine D1 antagonist SCH 23390, but not D2 antagonist YM 09151-2 or Clozapine, a drug with high affinity to D4 receptors, before nicotine injections, completely blocked Fos expression in the striatum. Nicotine induced Fos expression was also blocked completely by the NMDA receptor antagonists MK-801 and CPP. These results suggest that nicotine-induced Fos expression in the striatum is mediated mostly by dopamine D1 receptors and that the Fos expression is also dependent on N-methyl-D-aspartate (NMDA) stimulation.

Topics: Animals; Benzamides; Benzazepines; Clozapine; Corpus Striatum; Dizocilpine Maleate; Gene Expression Regulation; Genes, fos; Glutamates; Glutamic Acid; Male; Mecamylamine; Nicotine; Nucleus Accumbens; Piperazines; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, N-Methyl-D-Aspartate; Reward

The dopamine (DA) receptor regulating serotonin N-acetyltransferase (NAT) activity in chick retina was characterized pharmacologically. Intraocular (i.o.) administration of DA significantly decreased the nighttime NAT activity of chick retina. The effect of DA was antagonized by blockers of the D2 family of DA receptors, spiroperidol, YM-09151-2 and clozapine, and it was not affected by SCH23390, a selective antagonist of D1 DA receptor. Several agonists of D2 family of DA receptors given i.o. suppressed the nighttime NAT activity of the chick retina with quinpirole (D3/D4 receptor selective) and bromocriptine (D2/D3 receptor selective) being the most and the least potent drugs, respectively. The rank-order potency of antagonists of D2 family of DA receptors to block the inhibitory effect of quinpirole on the enzyme activity (with clozapine being relatively very potent, and (+)-butaclamol, raclopride and remoxipride-ineffective) match the characteristics of the D4 DA receptor. Moreover, although sulpiride effectively prevented the quinpirole-induced decline in the nighttime NAT activity of the chick retina, there was no marked stereoselectivity in its action. It is suggested that DA receptor regulating NAT activity in chick retina represents a D4-like subtype.

Topics: Animals; Arylamine N-Acetyltransferase; Benzamides; Benzazepines; Chickens; Circadian Rhythm; Clozapine; Dopamine; Dopamine Antagonists; Ergolines; Ketanserin; Male; Quinpirole; Receptors, Dopamine; Retina; Spiperone; Sulpiride

The radioligand [3H]YM-09151-2 ((+/-)-cis-N-(1-benzyl-2- methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylamino benzamide) was used to study the binding of various antipsychotic agents. Saturation experiments showed that [3H]YM-09151-2 labelled a single population of binding sites in both the olfactory tubercle and the striatum (dissociation constants (KD): 36 +/- 3 pM and 26 +/- 2 pM, respectively). The total number of binding sites (Bmax) was greater in the striatum than in the olfactory tubercle (18.1 +/- 1.8 fmol/mg tissue and 5.3 +/- 0.9 fmol/mg tissue respectively). Risperidone and thioridazine displaced [3H]YM-09151-2 in a biphasic manner in both brain regions, and clozapine also produced biphasic displacement curves in the olfactory tubercle but not in the striatum. All other dopamine D2 receptor antagonists tested displaced [3H]YM-09151-2 in a monophasic manner in both brain regions, in agreement with previously published data. Biphasic displacement did not appear to result from interactions with either the dopamine D3, dopamine D4, 5-HT2, 5-HT1C or the 5-HT1A receptor binding sites. It is suggested that thioridazine, risperidone and clozapine might discriminate between different affinity states and/or subtypes of the dopamine D2 receptor which may be different from the recently identified D2short and D2long receptors.

Topics: Animals; Antipsychotic Agents; Benzamides; Brain; Clozapine; Corpus Striatum; Dopamine D2 Receptor Antagonists; In Vitro Techniques; Isoxazoles; Male; Olfactory Pathways; Piperidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Risperidone; Spiperone; Thioridazine

In the mouse, the light-sensitive pool of cAMP can be eliminated in the dark by application of the dopamine D2-like receptor agonists LY 171555 (quinpirole), (+)-N0437 (2-[N-(n-propyl)-N-2-(thienylethylamino)-5-hydroxytetralin]) , or (+)-3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride]. The rank-order affinity of the ability of the D2-like antagonists to block the action of LY 171555 matched that of the rat D4 receptor. Reverse transcription of retina mRNA followed by DNA amplification using D4-specific nucleotides demonstrates the presence of D4 mRNA in retina. In situ hybridization studies using D4-specific digoxygenin-labeled oligonucleotides or 35S-labeled UTP RNA probes demonstrate the presence of D4 mRNA in the photoreceptor cell layer and in the inner nuclear and ganglion cell layers. The modulation by D4 ligands of the dark level of light-sensitive cAMP in photoreceptors demonstrates the physiological coupling of the D4 receptor subtype.

Topics: Adenylyl Cyclases; Animals; Base Sequence; Benzamides; Clozapine; Cyclic AMP; Ergolines; Gene Expression; In Situ Hybridization; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Sequence Data; Oligodeoxyribonucleotides; Polymerase Chain Reaction; Quinpirole; Receptors, Dopamine; Retina; RNA, Messenger; Spiperone

The actions in vitro of SCH 23390, YM 09151-2 and both enantiomers of 3-PPP on D-1 and D-2 dopamine receptors were investigated in superfused rat neostriatal slices. For comparison the following neuroleptics of different chemical classes were incorporated in our investigations: (+)-bulbocapnine, clozapine, chlorpromazine, cis-flupenthixol, (-)-sulpiride and haloperidol. The increase in the efflux of cyclic AMP was used as a measure for D-1 receptor stimulation. The decrease in the K+-evoked release of [3H]acetylcholine was used as measure of D-2 receptor stimulation. None of the drugs stimulated the D-1 receptor. Only (+)-3-PPP stimulated the D-2 receptor. All other drugs, including (-)-3-PPP, behaved as antagonists on the D-2 receptor, YM 09151-2 being the most potent. SCH 23390 was the most potent antagonist on the D-1 receptor. Haloperidol, cis-flupenthixol and (+)-bulbocapnine showed an appreciable D-1 receptor blocking potency in our model, whereas the other drugs were inactive. We found SCH 23390 to be the most D-1 selective antagonist although the drug still displayed considerable potency on the D-2 receptor. YM 09151-2 was the most D-2 selective antagonist.

Topics: 1-Methyl-3-isobutylxanthine; Acetylcholine; Animals; Antipsychotic Agents; Aporphines; Benzamides; Benzazepines; Caudate Nucleus; Chlorpromazine; Clozapine; Flupenthixol; Haloperidol; In Vitro Techniques; Male; Piperidines; Potassium; Putamen; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2